TR-14035

α4β7 and α4β1 integrins antagonist CAS# 232271-19-1

TR-14035

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Chemical structure

TR-14035

3D structure

Chemical Properties of TR-14035

Cas No. 232271-19-1 SDF Download SDF
PubChem ID 9912743 Appearance Powder
Formula C24H21Cl2NO5 M.Wt 474.33
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 41 mg/mL (86.44 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(2,6-dimethoxyphenyl)phenyl]propanoic acid
SMILES COC1=C(C(=CC=C1)OC)C2=CC=C(C=C2)CC(C(=O)O)NC(=O)C3=C(C=CC=C3Cl)Cl
Standard InChIKey DRSJLVGDSNWQBI-SFHVURJKSA-N
Standard InChI InChI=1S/C24H21Cl2NO5/c1-31-19-7-4-8-20(32-2)21(19)15-11-9-14(10-12-15)13-18(24(29)30)27-23(28)22-16(25)5-3-6-17(22)26/h3-12,18H,13H2,1-2H3,(H,27,28)(H,29,30)/t18-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of TR-14035

DescriptionTR-14035 is a a dual alpha4beta7(IC50=7 nM)/alpha4beta1 (IC50=87 nM) integrin antagonist . IC50 Value: alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM [1] Target: integrin TR14035 blocked the binding of human alpha(4)beta(7) to an (125)I-MAdCAM-Ig fusion protein with IC(50) values of 0.75 nM. TR14035 blocked binding of human alpha(4)beta(7)-expressing RPMI-8866 cells or murine mesenteric lymph node lymphocytes to MAdCAM-Ig with IC(50) values of 0.1 microM [2]. TR14035 blocked adhesion to HEVs [ED(50) of 0.01-0.1 mpk i.v.]. TR-14035 was taken up by rat and human hepatocytes by an apparently single saturable mechanism with K(m) of 6.7 and 2.1 microM, respectively, and taurocholate and digoxin reduced this uptake [3].

References:
[1]. Sircar I, et al. Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist. Bioorg Med Chem. 2002 Jun;10(6):2051-66. [2]. Egger LA, et al. Alpha(4)beta(7)/alpha(4)beta(1) dual integrin antagonists block alpha(4)beta(7)-dependent adhesion under shear flow. J Pharmacol Exp Ther. 2002 Jul;302(1):153-62.

TR-14035 Dilution Calculator

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Preparing Stock Solutions of TR-14035

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1082 mL 10.5412 mL 21.0824 mL 42.1647 mL 52.7059 mL
5 mM 0.4216 mL 2.1082 mL 4.2165 mL 8.4329 mL 10.5412 mL
10 mM 0.2108 mL 1.0541 mL 2.1082 mL 4.2165 mL 5.2706 mL
50 mM 0.0422 mL 0.2108 mL 0.4216 mL 0.8433 mL 1.0541 mL
100 mM 0.0211 mL 0.1054 mL 0.2108 mL 0.4216 mL 0.5271 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on TR-14035

TR-14035 is a dual antagonist of α4β7 and α4β1 integrins with IC50 value of 7nM and 87nM, respectively [1].

The inhibitors of α4β7 and α4β1 integrins are developed for treatment of inflammation and autoimmune diseases such as asthma and rheumatoid arthritis. TR-14035 is the first orally bioavailable chemical entity. It is screened out by the RPMI assay and the Jurkat cell adhesion assay. The IC50 values of it in Jurkat CS1 assay for α4β7 and α4β1 are 7nM and 87nM, respectively. Furthermore, the oral bioavailability of TR-14035 is limited due to the combination of dissolution rate, hepatic first-pass metabolism and biliary excretion. Besides that, TR-14035 displays species differences in the pharmacokinetics and disposition between the rat and dog [1, 2].

References:
[1] Sircar I, Gudmundsson K S, Martin R, et al. Synthesis and SAR of N-Benzoyl-l-Biphenylalanine Derivatives: Discovery of TR-14035, A Dual α4β7/α4β1 Integrin Antagonist. Bioorganic & medicinal chemistry, 2002, 10(6): 2051-2066.
[2] Tsuda-Tsukimoto M, Ogasawara Y, Kume T. Pharmacokinetics and metabolism of TR-14035, a novel antagonist of α4β1/α4β7 integrin mediated cell adhesion, in rat and dog. Xenobiotica, 2005, 35(4): 373-389.

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References on TR-14035

Pharmacokinetics and metabolism of TR-14035, a novel antagonist of a4ss1/a4ss7 integrin mediated cell adhesion, in rat and dog.[Pubmed:16019958]

Xenobiotica. 2005 Apr;35(4):373-89.

The pharmacokinetics and disposition of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (TR-14035), a novel a4ss1/a4ss7 antagonist, were investigated in the rat and dog. Results indicate extensive clearance of TR-14035 and low oral bioavailability, 17% and 13% in the rat and dog, respectively, at an oral dose of 10 mg/kg. At least 63% of the oral dose was absorbed from the gastrointestinal tract in the rat, and about one-third of the intravenous dose was excreted into bile as unchanged drug in the rat and dog. These data indicate that the oral bioavailability of TR-14035 was limited due to significant first-pass metabolism and biliary excretion in the liver. A species-dependent difference in metabolism was observed. The principal metabolite, O-desmethyl TR-14035, observed in rat, dog and probably human, was further conjugated with sulfate in the rat, but never in dog and human, based on in vitro metabolism and in vivo metabolite profile studies. Urinary excretion was a minor elimination route, but an interesting species difference was recognized. TR-14035 was reabsorbed from the rat renal proximal tubules, and by contrast, secreted into the tubules in the dog, probably via active transport systems.

Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist.[Pubmed:11937364]

Bioorg Med Chem. 2002 Jun;10(6):2051-66.

alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.

Role of human liver cytochrome P450 2C9 in the metabolism of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035.[Pubmed:15855725]

Drug Metab Pharmacokinet. 2005 Apr;20(2):127-34.

The metabolism of a novel dual antagonist for alpha4beta1/alpha4beta7 integrin, TR-14035, and the role of polymorphic enzyme responsible for this metabolism were investigated. Human liver microsomes catalyzed the NADPH-dependent metabolism of TR-14035 to a primary metabolite, O-desmethyl TR-14035. This formation was completely blocked by both sulfaphenazole, a selective CYP2C9 inhibitor, and CYP2C9 antibody, whereas potent inhibitors selective for other CYPs exhibited little effects. Of 12 recombinant CYPs examined, O-desmethyl metabolite was principally formed by CYP2C9. CYP1A1, an extrahepatic enzyme, also had this activity (about one-fourth of CYP2C9). Utilizing recombinant CYP2C9*1, K(m) and V(max)/K(m) values of 23.3 microM and 0.284 microL/min/pmol CYP2C9, respectively, were obtained for the O-desmethyl formation, which were quite similar to those in CYP2C9*2 enzyme. In contrast, V(max)/K(m) value in recombinant CYP2C9*3 was approximately one-sixth of CYP2C9*1 and *2. In agreement, kinetics studies using human liver microsomes with CYP2C9*1/*1, *2/*2 and *3/*3 genotypes revealed that the V(max)/K(m) value in *2/*2 microsomes was comparable to that in wild type microsomes, in contrast, that in *3/*3 microsomes was reduced. These results demonstrate CYP2C9 is a primary enzyme mediating the O-desmethylation of TR-14035 in human liver. In homozygotes of CYP2C9*3, the metabolic clearance of TR-14035 should be decreased compared with homozygotes of CYP2C9*1 or 2.

Characterization of hepatobiliary transport systems of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035.[Pubmed:16969695]

Pharm Res. 2006 Nov;23(11):2646-56.

PURPOSE: Our previous pharmacokinetic studies have demonstrated that TR-14035, a novel dual antagonist for alpha4beta1/alpha4beta7 integrin, selectively and strongly accumulated in the liver and was mainly excreted in bile as an unchanged drug. In the present study, we investigated the hepatobiliary transport system in detail. MATERIALS AND METHODS: Uptake by hepatocytes and organic anion transporting polypeptide (OATP)-expressing Xenopus laevis oocytes or Flp-In-293 cells was performed in vitro. Biliary excretion was investigated in mdr1a/b-knockout mice, Bcrp-knockout mice and Mrp2-defective Eisai hyperbilirubinemic rats (EHBRs). RESULTS: TR-14035 was taken up by rat and human hepatocytes by an apparently single saturable mechanism with K(m) of 6.7 and 2.1 microM, respectively, and taurocholate and digoxin reduced this uptake. OATP1B1/OATP-C and OATP1B3/OATP8 expressed in oocytes mediated the TR-14035 uptake with K(m) of 7.5 and 5.3 microM, respectively. OATP1B1*15, a genetic variant of OATP1B1, exhibited a decreased transport of TR-14035 compared with OATP1B1*1a. Biliary excretion and total body clearance of unchanged TR-14035 in EHBRs were significantly lower than those in normal rats, while there was no difference in the clearances between wild and mdr1a/b- or Bcrp-knockout mice. CONCLUSION: These results indicate that OATP1B1 and OATP1B3 are at least partly responsible for the accumulation of TR-14035 into hepatocytes, and Mrp2 principally mediates the biliary excretion of TR-14035. Furthermore, genetic polymorphisms of OATP1B1 may cause an interindividual variability in the pharmacokinetics of TR-14035.

Description

TR-14035 is a a dual alpha4beta7(IC50=7 nM)/alpha4beta1 (IC50=87 nM) integrin antagonist .

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